1. Field of the Invention
The substituted bicyclic pyrimidine compounds of the present invention are single agents that have both cytotoxic and antiangiogenic effects. The antiangiogenic effect is mediated via inhibition of vascular endothelial growth factor-2 (VEGFR2). The cytotoxic effect is mediated by tubulin inhibition. The compounds, pharmaceutical compositions comprising the compounds, or their salts, solvates, and hydrates thereof, overcome two clinically important tumor resistance mechanisms that limit the activity of microtubule targeting agents: expression of P-glycoprotein and βIII tubulin.
2. Description of the Background Art
Agents that interfere with microtubules are important antitumor agents. Tumor angiogenic mechanisms that are vital for tumor growth and metastasis are targeted by antiangiogenic agents. Antiangiogenic agents are usually not tumoricidal but are mainly cytostatic. Combination chemotherapy with antiangiogenic and cytotoxic agents have shown significant promise and several studies with such combinations are in progress in the clinic.